The hematopoietic system functions throughout the lifetime of an animal to produce cells of the myeloid, erythroid, and lymphoid lineages. Homeostasis is maintained by signals that regulate the cell's ability to proliferate and/or differentiate into the specific lineages. Leukemia can be viewed as a disease resulting from a breakdown in these interactions. Oncogenes cause leukemia by perturbing the cell's normal regulatory mechanisms, and in doing so influence the differentiation and/or proliferative capacity of the cells. Our objective is to understand how oncogene products interact with these normal regulatory mechanisms to cause leukemia. Erythroid cell transformation by the avian erythroblastosis virus (AEV) strain S13 provides a powerful model system to study oncogenes that affect the differentiation and/or proliferation of avian erythroid cells. Using this system we have two major objectives: to understand the mechanism of transformation of the S13 virally encoded oncogene v-sea, and to use a temperature-conditional mutant in the sea oncogene in combination with other oncogenes to study the mechanism of action of these oncogenes that affect erythroid transformation and differentiation but do not have the proliferative capability to cause erythroblastosis. Specifically we have the following aims: 1. To mutate the v-sea oncogene to identify functionally important regions that are necessary for their ability to transform cells. Mutants will be generated to address the importance of autophosphorylation, intracellular localization, multimerization, and C-terminal regulatory domains in transformation. 2. To characterize the cellular sea gene product and isolate full-length cDNA clones for this gene. Mutants will be generated to identify the mechanisms by which the c-sea gene can be activated such that it causes transformation. 3. To use the ts-sea oncogene in combination with either the v-rel or v-ski oncogenes to determine the mechanisms by which these two nuclear oncogenes affect erythroid differentiation. These mechanisms will be compared with those we have previously identified involving the v-erbA oncogene and the transferrin receptor.